Download 02 Cholesterol Metabolism2012-03-18 01:50617 KB

Cholesterol Metabolism
Dr. Usman Ghani
1 Lecture
Cardiovascular Block
Overview
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Introduction
Cholesterol structure
Cholesteryl esters
Cholesterol synthesis
Rate limiting step
Regulation of cholesterol synthesis
Regulation of HMG CoA reductase
Excretion of cholesterol
Hypercholesterolemia and treatment
Cholesterol
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Most important animal steroid
Maintains membrane fluidity
Insulating effect on nerve fibres
Cholesterol is the parent molecule for
– Bile acids and bile salts
– Steroid hormones
– Vitamin D3
Liver plays a central role
in the regulation of
cholesterol homeostasis
Cholesterol Structure
Cholesteryl esters
• Most plasma cholesterol is esterified with a
fatty acid
• CEs are not present in membranes
• Present in small amounts in most cells
• More hydrophobic than cholesterol
Cholesterol synthesis
• Synthesized in all tissues
• Major sites for synthesis: liver, adrenal cortex,
testes, ovaries and intestine
• All carbon atoms are derived from acetyl CoA
• Enzymes involved in biosynthesis are partly
located in ER and partly in cytoplasm
Synthesis of HMG CoA
• HMG CoA is present
in both cytosol and
mitochondria of liver
• Mitochondrialketogenesis
• Cytosolic –
cholesterol synthesis
Synthesis of mevalonic acid
• Rate limiting and key
step
• Occurs in cytosol
• HMG CoA reductase is
an ER membrane
enzyme with catalytic
unit hanging in the
cytosol
Further steps in synthesis
• Production of a 5-carbon unit:
– Isopentinyl pyrophosphate (IPP)
• Condensation to a 30C compound: squalene
• Cyclization of squalene to 30C lanosterol
• Synthesis of 27-Carbon cholesterol (defect in
this leads to Smith-Lemli-Opitz Syndrome)
Regulation of Cholesterol Synthesis
• HMG CoA reductase is the rate-limiting
enzyme of cholesterol synthesis
HMG CoA Reductase Regulation
Gene
Cholesterol
Transcription
Translation
Glucagon
Cortisones
Statins
HMG CoA Reductase
HMG CoA
Insulin
Thyroxin
Cholesterol
HMG CoA Reductase Regulation
• Sterol-dependent regulation of gene
expression
• Sterol-accelerated enzyme degradation
• Sterol-independent
phosphorylation/dephosphorylation
• Hormonal regulation
Sterol-dependent regulation of
gene expression of HMG CoA
• When sufficient cholesterol is present,
transcription is suppressed and vice versa
• Sterol Regulatory Element (SRE) is a
recognition sequence in the DNA
• SREBP (SRE binding protein) binding to SRE is
essential for transcription of this gene
• SREBP cleavage-activating protein (SCAP) is an
intracellular cholesterol sensor
Sterol-dependent regulation
Cholesterol High
• SCAP binds to insig protein
(insulin-induced protein) in
ER membrabe
• SCAP-SREBP is retained in
the ER
• Down regulation of
cholesterol synthesis
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Cholesterol Low
SCAP-SREBP moves to Golgi
bodies
SCAP is removed from
SREBP
SREBP binds to SRE in DNA
HMG CoA gene is activated
Enzyme phosphorylation and
dephosphorylation
• AMP- activated protein kinase (AMPK) for
phosphorylation
• Phosphorylated form of enzyme is inactive
• Dephosphorylated form is active
• High ATP  cholesterol synthesis stops
• Low ATP  cholesterol synthesis starts
Hormonal Regulation
• Insulin and thyroxine increase upregulation of
enzyme expression
• Glucagon and cortisol have opposite effect
Excretion of cholesterol
• By conversion into bile acids and bile saltsexcreted in the feces
– Secretion of cholesterol in bile
– Transported to intestine for elimination
• In the intestine, some cholesterol is converted
by bacteria into coprostanol and cholestanol
before excretion
Hypercholesterolemia
• High conc. of cholesterol in blood
• Leads to atherosclerosis
• Statin drugs are used to decrease plasma
cholesterol levels
• Statins are structural analogs of HMG CoA
reductase
• Statins inhibit enzyme activity by competitive
inhibition
b-Sitosterols/ Phytosterols
• Plant sterols and are poorly absorbed by
humans
• Block the absorption of dietary cholesterol
• Clinically useful in the dietary treatment of
hypercholesterolemia